Cyclohexene diol derivatives

ABSTRACT

The present invention relates to optically active cyclohexene diol derivatives and optically active cyclohexenone derivatives, and a process for production of these compounds in which a special cyclohexene diol of a starting material is reacted by selectively positioning transesterification in the presence of lipase to obtain an optically active cyclohexene diol derivative and then an optically active cyclohexenone derivative represented by the following formula: ##STR1## According to the present invention, optically active cyclohexene diol derivatives and optically active cyclohexenone derivatives, which are intermediates for synthesizing physiologically active materials, can be obtained efficiently.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the following optically activecyclohexene diol derivatives (1) and (1'), and optically activecyclohexenone derivatives (2) and (2'), and a process for production ofthese compounds.

2. Description of the Prior Art

The optically active cyclohexene diol derivatives represented by thefollowing formula (1) and (1') , and the optically active cyclohexenonederivatives represented by the following formula (2) and (2') are usefulas intermediates for synthesizing physiologically active compounds.

The optically active cyclohexenone derivatives represented by theformula (2), for example, can be used to obtain occidol (8) of asesquiterpene through six steps as shown in the following. ##STR2##

Further, the optically active cyclohexene diol derivative represented bythe formula (1) can be an intermediate for synthesizing compactin (19)which is a hyperlipemia therapeutic drug (HMG CoA reductase synthesisinhibitor) as shown in the following. ##STR3##

Though the compounds are useful as described above, these have not beenprepared by an efficient process.

As an example, optically active 5-trimethylsilyl cyclohex-2-enoneequivalent to the compounds of the present invention has been obtainedby a method comprising reacting the racemate with cinchonidine of analkaloid and toluenethiol and repeatedly recrystallizing the resultingdiastereomer salt. However, the method comprises several steps and theyield is too low (3%) so that such a production process is not efficient(Tetrahedron Lett., 28, 5669 (1987).

SUMMARY OF THE INVENTION

Considering these problems, the inventors of the present inventionearnestly studied to efficiently obtain pure optically activecyclohexenone derivatives useful as intermediates for synthesis ofphysiologically active materials. Then, they have found the opticallyactive cyclohexene diols represented by the following formulas (1) and(1'), and the optically active cyclohexenone derivatives represented bythe following formulas (2) and (2'), and the process for efficientlyproducing these compounds.

The present invention is characterized in that a cyclohexene diolrepresented by the formula: ##STR4## is used as a starting material toreact with an acylating agent in the presence of lipase by selectivelypositioning transesterification, and an optically active cyclohexenediol derivative represented by the formula: ##STR5## wherein R₁ isalkyl, is obtained from the above reaction, and then an optically activecyclohexenone derivative represented by the formula: ##STR6## isobtained. The reaction steps of the production method of the presentinvention are shown in the following as an example. ##STR7##

The cyclohexene diol (3) of a starting material in the present inventionis easily obtained by reducing a carbonyl group of the cyclohexenonederivative (22) obtained by a general Diels-Alder reaction, in which 1,3-cyclohexadiene (20) is reacted with hydroquinone (21), in the presenceof a reducing agent such as diisobutyl aluminum hydride.

The obtained cyclohexene diol (3) is reacted by selectively positioningtransesterification with an acylating agent in the presence of lipase,and then optically active cyclohexene diol derivatives (1) and (1') canbe obtained. As the acylating agent, fatty acid vinyl esters,triglycerides, acid anhydrides, esters are exemplified, and fatty acidvinyl esters are preferred. As the lipase, if it acts as a catalyst, anykinds of lipase may be used in any forms of purified enzyme powder,immobilized enzyme, microorganisms and the like. Particularly, lipasefrom a Pseudomonas genus, for example, commercially available lipase PS(trade name, manufactured by Amano Pharmaceutical Co. , Ltd. ) andTOYOBO lipase (trade name, manufactured by Toyobo Co., Ltd. ) arepreferred. As a reaction solvent, an organic solvent which does notinhibit the reaction can be preferably used, and more preferablyacetonitrile is used. Otherwise, the reaction may be conducted in thepresence of substrates without a solvent.

The optically active cyclohexene diol derivatives (1) and (1') can beconverted into the optically active cyclohexenone derivatives (2) and(2') by using, for example, bistriphenylphosphine palladium chloride.

By the above described process, the following merits are obtained.

1. It is possible to obtain efficiently, as optically pure compounds,optically active cyclohexene diol derivatives and optically activecyclohexenone derivatives which are useful for synthesis ofphysiologically active materials.

2. The optically active cyclohexene diol derivatives and opticallyactive cyclohexenone derivatives obtained by the process of the presentinvention can be converted to useful chiral elements. As describedabove, for example, these compounds may be starting materials of occidol(8) and compactin (19) .

3. The cyclohexene diol represented by formula (3) is a meso compound,so that the optically active cyclohexene diol derivatives obtained fromthe compound can be act as both enantiomers by classification of hydroxyand acyl groups.

DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate the present invention morespecifically, but these are not intended as a definition of the limitsof the invention.

EXAMPLE 1

To a solution of cyclohexene diol (formula (3) , 200 mg, 1.04 mmol) andvinyl acetate (0.3 ml, 3.36 mmol) in acetonitrile, lipase PS (100 mg)was suspended. The mixture was stirred for 25 days at room temperature.After the lipase was filtered off, the filtrate was concentrated underreduced pressure. The residue was subjected to a column chromatographover silica gel to obtain colorless solid monoacetate (formula (1'), 202mg, 83%). The specific rotation of the monoacetate was [α]_(D) ³⁰ -76.5°(c 1.02, CHCl₃). Further, the other physical property values were asfollows.

IR (film) 3444 cm⁻¹, 1737 cm⁻¹ ¹ H-NMR (90 MHz), CDCl₃ 1.16-1.70 (m,4H), 1.90 (s, 1H, D₂ O exchangeable), 2.03 (s, 3H), 2.26 (ddd, 2H,J=7.1, 5.4, 1.7 Hz), 2.42-2.79 (m, 2H), 4.14 (quint, 1H, J=5.4 Hz), 5.39(t, 1H, J=5.4 Hz), 5.96-6.48 (m, 4H) MS m/z 234 (M⁺), 80 (100%) HRMSCalculated for C₁₄ H₁₈ O₃, 234.1256 (M⁺), Found, 234.1240

EXAMPLE 2

To a solution (1 ml) of monoacetate (formula (1'), 146 mg, 0.624 mmol)in dichloromethane, triethylamine (0.35 ml, 2.5 mmol), DMAP (5 mg, 0.04mmol) and pivalonic anhydride (0.38 ml, 1.9 mmol) were added. Themixture was stirred for three days at room temperature. After addingwater, the mixture was extracted with dichloromethane. The organic layerwas washed with a saturated aqueous solution of sodium bicarbonate andthen with a saturated solution of sodium chloride, and dried overmagnesium sulfate. The solvent was distilled away under reducedpressure. The residue was subjected to a chromatograph over silica gelto obtain a pivalate. The compound was dissolved in methanol (3 ml), andpotassium carbonate was added and the mixture was stirred for one hour.Dichloromethane was added, and the mixture was washed with a saturatedaqueous solution of sodium chloride twice and dried over magnesiumsulfate. The solvent was distilled away under reduced pressure and theresidue was subjected to a chromatograph over silica gel to obtain thecolorless solid pivalate (formula (1) , 152 rag, 88%) . The specificrotation of the compound was [α]_(D) ³⁰ +99.3° (c 1.06, CHCl₃). Theother physical property values were as follows.

m.p. 72°-73° C. IR (nujol) 1731, 1695, 3488 cm⁻¹ ¹ H-NMR (90 MHz ),CDCl₃ 1.17 (s, 9H), 1.17-1.55 (m, 4H), 1.62 (s, 1H), 2.04-2.78 (m, 4H),4.13 (quint, 1H, J=5.6 Hz), 5.29 (t, 1H, J-5.4 Hz), 6.00-6.46 (m, 4H) MSm/z 276 (M⁺), 80 (100%) HRMS Calculated for C₁₇ H₂₄ O₃, 276.1725, Found,276.1725

EXAMPLE 3

To a solution (2 ml) of a monoacetate (formula (1'), 100 mg, 0.427 mmol)in acetonitrile, ammonium carbonate (41 mg) and bistriphenylphosphinepalladium chloride (3 mg, 0.004 mmol) were added, and the mixture wasrefluxed for 20 minutes. Diethyl ether was added to the reactionmixture. The solution was washed with a saturated aqueous solution ofsodium bicarbonate and then with an aqueous solution of sodium chloride.The organic layer was dried over magnesium sulfate. The solvent wasdistilled away under reduced pressure. The residue was subjected to achromatograph over silica gel to obtain the cyclohexenone derivative (62mg, 84% ) represented by formula (2). The physical property values wereas follows. The specific rotation of the compound was [α]_(D) ³² -147°(c0.41, CHCl₃) . The other physical property values were as follows.

m.p. 46.5°-47.5° C. IR (nujol) 1650 cm⁻¹ ¹ H-NMR (90 MHz), CDCl₃1.11-1.69 (m, 4H), 1.73-2.26 (m, 1H), 2.27-2.67 (m, 4H), 3.09 (br. s,1H), 5.79 (ddd, 1H, J=10.2, 2.5, 1.7 Hz), 6.03-6.35 (m, 2H), 6.56-6.78(m, 1H) MS m/z 174 (M⁺), 80 (100%) HRMS Calculated for C₁₂ H₁₄ O,174.1045, Found, 174.1059

EXAMPLE 4

The same method as in Example 3 was used except that pivalate (formula(1), 99 mg, 0.359 mmol), ammonium carbonate (3 4 mg, 0.54 mmol ),triphenylphosphine palladium chloride (2.5 mg, 0.0035 mmol) andacetonitrile 3 mg were used to obtain the cyclohexenone derivative(formula (2'), 49 mg, 79%). The specific rotation was [α]_(D) ³¹ +144.6°(c 0.418, CHCl₃). The melting point was as follows. m.p. 46°-47° C.

In addition, the optical purity was >99% ee by using optical resolutionHPLC (trade name, CHIRAL CEL OB, effluent: i-PrOH/hexane=1/9) .

We claim:
 1. An optically active cyclohexene diol derivative representedby the general formula: ##STR8## wherein R₁ is alkyl.
 2. An opticallyactive cyclohexenone derivative represented by the formula: ##STR9##